Enrolled at Columbia as a physics student, De Palma became enraptured with the filmmaking process after viewing Citizen Kane and Vertigo. De Palma subsequently enrolled at the newly coed Sarah Lawrence College as a graduate student in their theater department in the early 1960s, becoming one of the first male students among a female population. Once there, influences as various as drama teacher Wilford Leach, the Maysles brothers, Michelangelo Antonioni, Jean-Luc Godard, Andy Warhol and Alfred Hitchcock impressed upon De Palma the many styles and themes that would shape his own cinema in the coming decades. An early association with a young Robert De Niro resulted in The Wedding Party. The film, which was co-directed with Leach and producer Cynthia Munroe, had been shot in 1963 but remained unreleased until 1969, when De Palma's star had risen sufficiently within the Greenwich Village filmmaking scene. De Niro was unknown at the time; the credits mistakenly display his name as "Robert Denero." The film is noteworthy for its invocation of silent film techniques and an insistence on the jump-cut for effect. De Palma followed this with various small films for the NAACP and The Treasury Department.

During the 1960s, De Palma began making a living producing documentary films, notably The Responsive Eye, a 1966 movie about The Responsive Eyeop-art exhibit curated by William Seitz for Museum of Modern Art in 1965. In an interview with Gelmis from 1969, De Palma described the film as "very good and very successful. It's distributed by Pathe Contemporary and makes lots of money. I shot it in four hours, with synched sound. I had two other guys shooting people's reactions to the paintings, and the paintings themselves."[3]

Dionysus in 69 (1969) was De Palma's other major documentary from this period. The film records The Performance Group's performance of Euripides' The Bacchae, starring, amongst others, De Palma regular William Finley. The play is noted for breaking traditional barriers between performers and audience. The film's most striking quality is its extensive use of the split-screen. De Palma recalls that he was "floored" by this performance upon first sight, and in 1973 recounts how he "began to try and figure out a way to capture it on film. I came up with the idea of split-screen, to be able to show the actual audience involvement, to trace the life of the audience and that of the play as they merge in and out of each other."[4]

Greetings is about three New Yorkers dealing with the draft. The film is often considered the first to deal explicitly with the draft. The film is noteworthy for its use of various experimental techniques to convey its narrative in ultimately unconventional ways. Footage was sped up, rapid cutting was used to distance the audience from the narrative, and it was difficult to discern with whom the audience must ultimately align. "Greetings" ultimately grossed over $1 million at the box office and cemented De Palma's position as a bankable filmmaker.

After the success of his 1968 breakthrough, De Palma and his producing partner, Charles Hirsch, were given the opportunity by Sigma 3 to make an unofficial sequel of sorts, initially entitled Son of Greetings, and subsequently released as Hi, Mom!. While "Greetings" accentuated its varied cast, Hi, Mom! focuses on De Niro's character, Jon Rubin, an essential carry-over from the previous film. The film is ultimately significant insofar as it displays the first enunciation of De Palma's style in all its major traits – voyeurism, guilt, and a hyper-consciousness of the medium are all on full display, not just as hallmarks, but built into this formal, material apparatus itself.

These traits come to the fore in Hi, Mom!'s "Be Black, Baby" sequence. This sequence parodies cinéma vérité, the dominant documentary tradition of the 1960s, while simultaneously providing the audience with a visceral and disturbingly emotional experience. De Palma describes the sequence as a constant invocation of Brechtian distanciation: “First of all, I am interested in the medium of film itself, and I am constantly standing outside and making people aware that they are always watching a film. At the same time I am evolving it. In Hi, Mom! for instance, there is a sequence where you are obviously watching a ridiculous documentary and you are told that and you are aware of it, but it still sucks you in. There is a kind of Brechtian alienation idea here: you are aware of what you are watching at the same time that you are emotionally involved with it.”

"Be Black, Baby" was filmed in black and white stock on 16 mm, in low-light conditions that stress the crudity of the direct cinema aesthetic. It is precisely from this crudity that the film itself gains a credibility of “realism.” In an interview with Michael Bliss, De Palma notes “[Be Black, Baby] was rehearsed for almost three weeks... In fact, it's all scripted. But once the thing starts, they just go with the way it's going. I specifically got a very good documentary camera filmmaker (Robert Elfstrom) to just shoot it like a documentary to follow the action." Furthermore, "I wanted to show in Hi, Mom! how you can really involve an audience. You take an absurd premise – "Be Black, Baby" – and totally involve them and really frighten them at the same time. It's very Brechtian. You suck 'em in and annihilate 'em. Then you say, "It's just a movie, right? It's not real." It's just like television. You're sucked in all the time, and you're being lied to in a very documentary-like setting. The "Be Black, Baby" section of Hi, Mom! is probably the most important piece of film I've ever done."

In the 1970s, De Palma went to Hollywood where he worked on bigger budget films. In 1970, De Palma left New York for Hollywood at age thirty to make Get to Know Your Rabbit, starring Orson Welles and Tommy Smothers. Making the film was a crushing experience for De Palma as Tommy Smothers didn't like a lot of De Palma's ideas.[7]

After several small, studio and independent released films that included stand-outs Sisters, Phantom of the Paradise, and Obsession, a small film based on a novel called Carrie was released directed by Brian De Palma. The psychic thriller Carrie is seen by some as De Palma's bid for a blockbuster. In fact, the project was small, underfunded by United Artists, and well under the cultural radar during the early months of production, as Stephen King's source novel had yet to climb the bestseller list. De Palma gravitated toward the project and changed crucial plot elements based upon his own predilections, not the saleability of the novel. The cast was young and relatively new, though the stars Sissy Spacek and John Travolta had gained considerable attention for previous work in, respectively, film and episodic sitcoms. Carrie became a hit, the first genuine box-office success for De Palma. It garnered Spacek and Piper Laurie Oscar nominations for their performances. Preproduction for the film had coincided with the casting process for George Lucas's Star Wars, and many of the actors cast in De Palma's film had been earmarked as contenders for Lucas's movie, and vice-versa.[8] The "shock ending" finale is effective even while it upholds horror-film convention, its suspense sequences are buttressed by teen comedy tropes, and its use of split-screen, split-diopter and slow motion shots tell the story visually rather than through dialogue.

The financial and critical success of Carrie allowed De Palma to pursue more personal material. The Demolished Man was a novel that had fascinated De Palma since the late 1950s and appealed to his background in mathematics and avant-garde storytelling. Its unconventional unfolding of plot (exemplified in its mathematical layout of dialogue) and its stress on perception have analogs in De Palma's filmmaking. He sought to adapt it on numerous occasions, though the project would carry a substantial price tag, and has yet to appear onscreen (Steven Spielberg's adaptation of Philip K. Dick's Minority Report bears striking similarities to De Palma's visual style and some of the themes of The Demolished Man). The result of his experience with adapting The Demolished Man was The Fury, a science fiction psychic thriller that starred Kirk Douglas, Carrie Snodgress, John Cassavetes and Amy Irving. The film was admired by Jean-Luc Godard, who featured a clip in his mammoth Histoire(s) du cinéma, and Pauline Kael who championed both The Fury and De Palma. The film boasted a larger budget than Carrie, though the consensus view at the time was that De Palma was repeating himself, with diminishing returns. As a film it retains De Palma's considerable visual flair, but points more toward his work in mainstream entertainments such as The Untouchables and Mission: Impossible, the thematic complex thrillers for which he is now better known.

For many film-goers, De Palma's gangster films, most notably Scarface and Carlito's Way, pushed the envelope of violence and depravity, and yet greatly vary from one another in both style and content and also illustrate De Palma's evolution as a film-maker. In essence, the excesses of Scarface contrast with the more emotional tragedy of Carlito's Way. Both films feature Al Pacino in what has become a fruitful working relationship. In 1984, he directed the music video of Bruce Springsteen's song "Dancing in the Dark".

Later into the 1990s and 2000s, De Palma did other films. He attempted to do dramas and a few thrillers plus science fiction. Some of these movies (Mission: Impossible, Carlito's Way) worked and some others (Mission to Mars, Raising Cain, Snake Eyes, The Bonfire of the Vanities) failed at the box office. Of these films, The Bonfire of the Vanities would be De Palma's biggest box office disaster, losing millions. Another later movie from De Palma, Redacted, unleashed a controversy over its subject of American involvement in Iraq, and supposed atrocities committed there. It received limited release in the United States.

De Palma's films can fall into two categories, his psychological thrillers (Sisters, Body Double, Obsession, Dressed to Kill, Blow Out, Raising Cain) and his mainly commercial films (Scarface, The Untouchables, Carlito's Way, and Mission: Impossible). He has often produced "De Palma" films one after the other before going on to direct a different genre, but would always return to his familiar territory. Because of the subject matter and graphic violence of some of De Palma's films, such as Dressed to Kill, Scarface and Body Double, they are often at the center of controversy with the Motion Picture Association of America, film critics and the viewing public.[10]

De Palma is known for quoting and referencing other director's work throughout his career. Michelangelo Antonioni's Blowup and Francis Ford Coppola's The Conversation plots were used for the basis of Blow Out. The Untouchables '​ finale shoot out in the train station is a clear borrow from the Odessa Steps sequence in Sergei Eisenstein's The Battleship Potemkin. The main plot from Rear Window was used for Body Double, while it also used elements of Vertigo. Vertigo was also the basis for Obsession. Dressed to Kill was a note-for-note homage to Hitchcock's Psycho, including such moments as the surprise death of the lead actress and the exposition scene by the psychiatrist at the end.[10]

Film critics have often noted De Palma's penchant for unusual camera angles and compositions throughout his career. He often frames characters against the background using a canted angle shot. Split-screen techniques have been used to show two separate events happening simultaneously.[10] To emphasize the dramatic impact of a certain scene De Palma has employed a 360-degree camera pan. Slow sweeping, panning and tracking shots are often used throughout his films, often through precisely-choreographed long takes lasting for minutes without cutting. Split focus shots, often referred to as "di-opt", are used by De Palma to emphasize the foreground person/object while simultaneously keeping a background person/object in focus. Slow-motion is frequently used in his films to increase suspense.[10]

De Palma previously dated Margot Kidder in the early 1970s. He has been married and divorced three times, to actress Nancy Allen (1979–1983), producer Gale Anne Hurd (1991–1993), and Darnell Gregorio (1995–1997). He has one daughter from his marriage to Gale Anne Hurd, Lolita de Palma, born in 1991, and one daughter from his marriage to Darnell Gregorio, Piper De Palma, born in 1996. He resides in Manhattan, New York.[11]

De Palma has encouraged and fostered the filmmaking careers of directors such as Quentin Tarantino, Mark Romanek and Keith Gordon. Tarantino said – during interview with De Palma, that Blow Out is one of his all time favourite films, and that after watching Scarface he knew how to make his own film. Terrence Malick credits seeing De Palma's early films on college campus tours as a validation of independent film, and subsequently switched his attention from philosophy to filmmaking.

Critics who frequently admire De Palma's work include Pauline Kael, Roger Ebert and Armond White, among others. Kael wrote in her review of Blow Out, "At forty, Brian De Palma has more than twenty years of moviemaking behind him, and he has been growing better and better. Each time a new film of his opens, everything he has done before seems to have been preparation for it."[15] In his review of Femme Fatale, Roger Ebert wrote about the director: "De Palma deserves more honor as a director. Consider also these titles: Sisters, Blow Out, The Fury, Dressed to Kill, Carrie, Scarface, Wise Guys, Casualties of War, Carlito's Way, Mission: Impossible. Yes, there are a few failures along the way (Snake Eyes, Mission to Mars, The Bonfire of the Vanities), but look at the range here, and reflect that these movies contain treasure for those who admire the craft as well as the story, who sense the glee with which De Palma manipulates images and characters for the simple joy of being good at it. It's not just that he sometimes works in the style of Hitchcock, but that he has the nerve to."[13] White said in defense of De Palma's Mission to Mars, "[The film] is a litmus test. It can be said with certainty that any reviewer who pans it does not understand movies, let alone like them."[16]

Julie Salamon has written that "[De Palma] was: a perverse misogynist."[14] De Palma has responded to accusations of misogyny by saying: "I'm always attacked for having an erotic, sexist approach-- chopping up women, putting women in peril. I'm making suspense movies! What else is going to happen to them?"

David Thomson wrote in his entry for De Palma, "There is a self-conscious cunning in De Palma's work, ready to control everything except his own cruelty and indifference."[17]